Bone fractures due to osteoporosis present a significant public health burden, high medical costs, and reduced quality of life in an increasingl aged population. It is estimated that 40-90% of variation in BMD may be due to genetic variability. Although more than 40 candidate genes for predisposition to osteoporosis have been identified, they represent less than 1% of the genetic variance of BMD at the population level, due to the large number of genes functioning in bone development and homeostasis. These studies identify osteoporosis as a major health problem, and emphasize the need for further research and better animal models to elucidate genetic factors underlying this disease. In the proposed studies, we will define the molecular and developmental nature of the newly identified zebrafish osteopenia mutant, droog(dro)tft92N, as a novel animal model for human osteoporosis. This research is significant and innovative in that it may implicate a new gene in the prevention of osteoporosis. In addition, these studies will validate the zebrafish mutant dro as a new model to improve our understanding of the genetic contributions leading to human osteoporosis, and as an in vivo screening tool to identify new therapeutic targets to treat human osteoporosis. Our proposed studies to establish a three dimensional (3D) in vitro cell culture model to study normal and dro mutant harvested cells will provide an innovative platform for small molecular screens to identify novel therapies for improved and effective treatment of human osteoporosis.